Acquired Immune Deficiency Syndrome (AIDS) has become recognized as one of the most catastrophic diseases to confront humanity. The etiologic agent of this disease is a lymphotrophic retrovirus referred to as human immunodeficiency virus (HIV-1) (Fauci, Science, 1988, 239. 617). Other retroviruses related to HIV-1 are also being identified. A few synthetic modified nucleosides have shown some promise in studies involving AIDS or AIDS-related complex (ARC) (Mitsuya et al, Proc. Natl. Acad. Sci. USA, 1985, 82. 7096; 1986, 83. 1911; DeClercq, J. Med. Chem., 1986, 29. 1561, Nair et al, J. Am. Chem. Soc., 1989, 111. 8502; Yarchoan et al, Science, 1989; 245. 412, Mitsuya et al, Science, 1990, 249, 1533). These include 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA), and 2',3'-dideoxyinosine (ddI). The antiviral activity of these compounds is associated with their ability to inhibit, in their phosphorylated triphosphate forms, a key enzyme in the virus life cycle, i.e. reverse transcriptase (Mitsuya et al, Proc. Natl. Acad. Sci. USA, 1987, 84. 2033). According to Broder and coworkers (Biochem. Pharmacol., 1987, 36 1765), ddA is superior to ddC and AZT in terms of therapeutic index. However, the therapeutic efficacy of ddA is limited by its instability, both with respect to rapid enzymatic deamination by the ubiquitous mammalian enzyme, adenosine deaminase, and hydrolytic cleavage of the glycosidic bond (Balzarini et al, Biochem. Biophys. Res. Commun., 1987, 145. 277; Nair et al, J. Org. Chem. 1990, 55. 3695. Other anti-HIV active dideoxynucleosides also suffer from the disadvantage of hydrolytic instability. There is, therefore, a critical need for the development of dideoxynucleosides with anti-HIV activity but with greater hydrolytic and enzymatic stability than ddA and other dideoxynucleosides.
The primary objective of the present invention is to provide dideoxynucleosides with anti-HIV activity with increased hydrolytic and enzymatic stability in comparison with ddA and other dideoxynucleosides.
Another objective of the present invention is to provide pharmaceutical compositions which contain compounds of the present invention in a hydrolytically and enzymatically stable environment, and which can be used as effective non toxic antiviral treating agents.
The yet further objective of the present invention is to provide a method of preparation of the compounds of the present invention and the pharmaceutical compositions of the present invention.
The objective of the present invention disclosure is concerned with the development of a series of new 2'-isodideoxy-.beta.-D-nucleosides and their derivatives that are hydrolytically very stable so that they would have enhanced therapeutic potential as antiviral agents, in particular as anti-HIV agents.
A further objective is to provide effective and direct routes to the synthesis of these isodideoxy-D-nucleosides and their derivatives.
A still further objective of the present invention is to provide therapeutic compositions containing the stable compounds of this invention.
The method and manner of accomplishing each of the above objectives of the invention will become apparent from the detailed description as set forth below.